Host proteases as determinants of coronaviral neurotropism and virulence.

To the Editor:

Recently, the study by Wu et al. (2020) presented a concise report on the epidemiological and molecular underpinnings of coronaviral neurotropism, and their potential implications for COVID-19 disease phenotypes. The report presented by the authors covers an important aspect of coronaviral infections, that may be increasingly recognized as COVID-19′s clinical phenotypes expand. An equally important parameter of coronaviral nervous system involvement that was not covered in this paper, despite being directly implied by its aim, was the interaction between host and virus at protease cleavage sites, as a determinant of neurotropism and virulence.

Spike protein cleavage at specific residues by host proteases is considered a priming step during SARS coronaviral infection, subsequently determining adsorption, tissue tropism and host compatibility (Millet and Whittaker, 2015). Despite the genomic similarities with other betacoronaviruses, including SARS-CoV, SARS-CoV-2 was recently shown to contain a unique furin-like cleavage site in its spike protein (Coutard et al., 2020). Interactions between host furin-like proteases and furin-like cleavage sites have been previously shown to be important determinants of neurotropism in other coronaviridae, with cleavage status determining disease phenotype (Cheng et al., 2019;11(10).). Interestingly, in a murine model examining the neurotropic potential of the human coronavirus strain O43 (HCoV-O43), a furin-protease gain-of-function mutation did not impact neuroinvasion, but did affect viral egress, producing a more indolent and correspondingly persistent pathogen within the CNS (Le coupanec et al., 2015).

Declarations

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable/Single Author.

Availability of data and materials: Not applicable.

Competing interests: None declared.

Funding: No funding source.

Authors' contributions: Single Author.

Acknowledgements: To Dr Maria Chatzi MD, for her guidance and updates on the literature.